Case-Crossover Design for Assessing Associations With Short-Term, Intermediate-Term, and Long-Term Exposures

The case-crossover design is a widely applicable design for observational studies. Its major advantages include robustness against unmeasured time-invariant and slowly varying confounders, as well as high statistical efficiency, both attributable to its self-controlled nature.

In this tutorial, we illustrate applications of the case-crossover design not only for assessing associations with short-term exposures, for which it was originally developed, but also for intermediate- and long-term exposures, using examples from our published studies. We further discuss key methodological considerations for its practical implementation.

We presented two subtypes of the case-crossover design, time-stratified and symmetric bidirectional, illustrated through examples of published studies evaluating the associations between air pollution exposures and the risk of hypertension hospitalization. As the exposure time frame extends from short to long term, the ability of the case-crossover design to inherently adjust for slowly varying confounders through self-matching diminishes. Consequently, additional confounders should be included in the regression model. Several considerations are important when using the case-crossover design: first, analyses are restricted to discordant individuals whose exposures differ between the case and control periods; second, there should be no underlying time trend in exposure within the time scheme of case and control periods.

Despite these limitations, the case-crossover design remains an attractive method for observational studies as it inherently adjusts for unmeasured time invariant and slowly varying confounders, such as genetics. While the examples focus on air pollution, the broad applicability of the case-crossover design makes it a valuable approach in various fields, including clinical research.